Abstract
We investigated the yield and distribution of macrocyclic products formed in combinatorial libraries (CLs) obtained via double-amidation reactions of methyl diesters with α,ω-diamines. The application of the static combinatorial chemistry (SCC) approach allowed us to generate a large number of macrocyclic diamides and tetraamides in single experiments. We show that high-pressure conditions accelerate the macrocyclization process but also have a great impact on the distribution of macrocyclic products in the presented libraries, promoting the formation of macrocyclic compounds and eliminating the linear ones. The distribution of macrocyclic products was also found to be strongly dependent on the structural features of the substrates employed. Furthermore, in three- and four-substrate CLs we observed the formation of a new type of hybrid tetraamides consisting of three different components.
Highlights
Pressure is one of the main factors, apart from temperature, that affect the direction and rate of chemical reactions.Principally, conducting a chemical transformation under highpressure conditions is beneficial for entropy reasons, which are crucial in the preorganization processes
Reactions characterized by a negative activation volume (ΔV* < 0) are accelerated by pressure, whereas those with ΔV* > 0 are inhibited.[1−3] this strategy has proved to be useful for reactions that are inefficient under thermal conditions for steric or stereoelectronic reasons.[4−9] To date, the remarkable input of the high-pressure technique has been observed in reactions such as condensation, addition, and elimination, in various type of cycloadditions,[10] and in organocatalysis[11,12] as well as in metal catalysis.[13−16] In addition to the high-dilution technique,[17,18] template effects,[19−21] and metathesis,[22,23] high pressure is valuable tool in the macrocyclization process, since it prevents unfavorable entropy effects, accelerates the formation of cyclic products, and eliminates the linear ones
We recently demonstrated that inorganic salts have a great impact on the formation of macrocyclic benzoamides via the double-amidation reaction of methyl dicarboxylic esters with α,ω-diamines.[52]
Summary
Pressure is one of the main factors, apart from temperature, that affect the direction and rate of chemical reactions. The direction of chemical reactions carried out under high-pressure conditions is determined by the volume of activation, defined as the difference between the molar volumes of the transition state and substrates (ΔV* = VTS − VS). We demonstrate representative examples of the effect of high pressure on the formation of combinatorial libraries. This approach is a relatively unexplored area of chemistry, it can afford several practical advantages in the challenging synthesis of macrocyclic compounds
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